Anticancer Chemo Research Articles

Мелатонин и мужское бесплодие, вызванное окислительным стрессом

Among couples unable to conceive a child, infertility is explained by the male factor in about 50% of cases. The etiology of male infertility remains uncertain in 30-50% of patients. One of the frequent etiological factors of male infertility is oxidative stress, a statusin which an unbalance between the production of reactive oxygen species and the mechanisms of antioxidant protection. Today, the term «male oxidative stressinfertility» has been proposed as a new descriptor for infertile men with a combination of abnormalsperm characteristics and oxidative stress. Along with the use of traditional antioxidants, it is necessary to search for new moleculesto combat oxidative stressin infertile men. A promising strategy is to use melatonin, a hormone secreted by the pineal gland, as an antioxidant. The review examinesthe antioxidant effects of the melatonin metabolic cascade. The results ofstudies on the relationship between the level of melatonin in seminal plasma and male fertility are presented. New scientific data on the protective potential of melatonin against oxidative stress caused by various metabolic disorders, anticancer chemo- and radiation therapy and other pathogenetic conditions and negative effects are presented. The research on the prospects of using melatonin to protectspermatozoa from oxidative damage in the implementation of assisted reproductive technologiesis analyzed. The interim results ofstudies on the possibility of using melatonin as a dietary supplement in infertile men are summarized.

Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A.

Drug resistance is a major problem associated with anticancer chemo- and immunotherapies. Recent advances in the understanding of resistance mechanisms have revealed that enzymes of the APOBEC3 (A3) family contribute to the development of drug resistance in multiple cancers. A3 enzymes are polynucleotide cytidine deaminases that convert cytosine to uracil (C→U) in single-stranded DNA (ssDNA) and in this way protect humans against viruses and mobile retroelements. On the other hand, cancer cells use A3s, especially A3A and A3B, to mutate human DNA, and thus by increasing rates of evolution, cancer cells escape adaptive immune responses and resist drugs. However, as A3A and A3B are non-essential for primary metabolism, their inhibition opens up a strategy to augment existing anticancer therapies and suppress cancer evolution. To test our hypothesis that pre-shaped ssDNA mimicking the U-shape observed in ssDNA-A3 complexes can provide a better binder to A3 enzymes, a Cu(I)-catalyzed azide-alkyne cycloaddition was used to cross-link two distant modified nucleobases in ssDNA. The resultant cytosine-containing substrate, where the cytosine sits at the apex of the loop, was deaminated faster by the engineered C-terminal domain of A3B than a standard, linear substrate. The cross-linked ssDNA was converted into an A3 inhibitor by replacing the 2'-deoxycytidine in the preferred TCA substrate motif by 2'-deoxyzebularine, a known inhibitor of single nucleoside cytidine deaminases. This strategy yielded the first nanomolar inhibitor of engineered A3BCTD and wild-type A3A (Ki = 690 ± 140 and 360 ± 120 nM, respectively), providing a platform for further development of powerful A3 inhibitors.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Biological Carriers for Drug Delivery in Cancer Therapy.

Cancer is the second leading cause of death worldwide, with 10.0 million cancer deaths in 2020. Despite advances in targeted therapies, some pharmacological drawbacks associated with anticancer chemo and immunotherapeutic agents include high toxicities, low bioavailability, and drug resistance. In recent years, extracellular vesicles emerged as a new promising platform for drug delivery, with the advantage of their inherent biocompatibility and specific targeting compared to artificial nanocarriers, such as liposomes. Particularly, mesenchymal stem/stromal cells were proposed as a source of extracellular vesicles for cancer therapy because of their intrinsic properties: high in vitro self-renewal and proliferation, regenerative and immunomodulatory capacities, and secretion of extracellular vesicles that mediate most of their paracrine functions. Moreover, extracellular vesicles are static and safer in comparison with mesenchymal stem/stromal cells, which can undergo genetic/epigenetic or phenotypic changes after their administration to patients. In this review, we summarize currently reported information regarding mesenchymal stem/stromal cell-derived extracellular vesicles, their proper isolation and purification techniques - from either naive or engineered mesenchymal stem/stromal cells - for their application in cancer therapy, as well as available downstream modification methods to improve their therapeutic properties. Additionally, we discuss the challenges associated with extracellular vesicles for cancer therapy, and we review some preclinical and clinical data available in the literature.

CMTM6 as a master regulator of PD-L1.

Immune checkpoint proteins, such as programmed cell death receptor 1 (PD-1) and its ligand (PD-L1), play critical roles in the pathology of chronic inflammatory pathological conditions, particularly cancer. In addition, the activation of PD-1/PD-L1 pathway is involved in mediating resistance to certain anti-cancer chemo- and immuno-therapeutics. Unfortunately, targeting the PD-1/PD-L1 pathway by the available anti-PD-1/PD-L1 drugs can benefit only a small proportion of cancer patients. Thus, studying the factors that regulate the expression of these immune checkpoint proteins is of central importance in this context. Recent investigations have identified CMTM6 and, to a lesser extent, CMTM4, as master regulators of PD-L1 expression in various cancer cells. Understanding the mechanisms by which such proteins upregulate the expression of PD-L1 in tumor cells, and determining the potential regulators of CMTM6 expression in different types of cancers will accelerate the development of new therapeutic targets and/or lead to the enhancement of the currently available PD-1/PD-L1 blockade therapies.

Effects of an Indomethacin Oral Spray on Pain Due to Oral Mucositis in Cancer Patients Treated With Radiotherapy and Chemotherapy: A Double-Blind, Randomized, Placebo-Controlled Trial (JORTC-PAL04)

ContextOral mucositis (OM) pain due to anticancer chemo- and radiotherapy has a very negative impact on patient quality of life. However, no high-quality studies have been performed regarding the analgesic efficacy of indomethacin (IM) oral spray for OM pain. ObjectivesThis randomized, placebo-controlled, double-blind trial aimed to evaluate the analgesic efficacy of IM oral spray for OM pain due to anticancer chemo- and radiotherapy. MethodsFrom July 2015 to December 2016, we enrolled adult cancer patients with OM pain that was due to anticancer chemo- or radiotherapy and was rated 4 or higher on Brief Pain Inventory (BPI) Item 5. Patients were randomly assigned in a 1:1 ratio to receive either IM oral spray or placebo.The primary endpoint was the change in the BPI Item 6 (“current pain”) score from before to 30 minutes after treatment. Secondary endpoints were the areas under the curves of BPI Item 6 at 15, 60, 120, 180, and 240 minutes after treatment; five items related to meals and conversation from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, Head and Neck Module 35; the Clinical Global Impressions-Improvement (CGI-I) scale; and adverse events. ResultsA total of 60 patients were assigned to receive IM oral spray (n = 33) or placebo spray (n = 27). The average change in the BPI item 6 score from before to 30 minutes after treatment was −1.85 (95% confidence interval: −2.37 to −1.32) in the IM spray group and −0.59 (−1.02 to −0.16) in the placebo group, indicating a significant difference (−1.26, −1.94 to −0.57, P < 0.01). The pain improvement persisted for 180 minutes. The intergroup differences in ability to drink liquids, ease in conversing, and CGI-I were all significant (P = 0.03, P = 0.02, and P < 0.01, respectively). No serious adverse events were reported. ConclusionIM oral spray alleviated short-term OM pain due to anticancer chemo- and radiotherapy, and may reduce the difficulty in eating meals.

Cyclic gomesin, a stable redesigned spider peptide able to enter cancer cells

Anticancer chemo- and targeted therapies are limited in some cases due to strong side effects and/or drug resistance. Peptides have received renascent interest as anticancer therapeutics and are currently being considered as alternatives and/or as complementary to biologics and small-molecule drugs. Gomesin, a disulfide-rich host defense peptide expressed in the Brazilian spider Acanthoscurria gomesiana selectively targets and disrupts cancer cell membranes. In the current study, we employed a range of biophysical methodologies with model membranes and bioassays to investigate the use of a cyclic analogue of gomesin as a drug scaffold to internalize cancer cells. We found that cyclic gomesin can internalize cancer cells via endocytosis and direct membrane permeation. In addition, we designed an improved non-disruptive and non-toxic cyclic gomesin analogue by incorporating D-amino acids within the scaffold. This improved analogue retained the ability to enter cancer cells and can be used as a scaffold to deliver drugs. Efforts to investigate the internalization mechanism used by host defense peptides, and to improve their stability, potency, selectivity and ability to permeate cancer cell membranes will increase the opportunities to repurpose peptides as templates for designing alternative anticancer therapeutic leads.

Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation.

Hypoxia, a common feature of solid tumours’ microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the microenvironment acidosis, represents a valuable target for drug strategy against advanced solid tumours. To overcome cancer cell resistance and improve the efficacy of therapeutics, the use of bio-reducible prodrugs also known as Hypoxia-activated prodrugs (HAPs), represents an interesting strategy to be applied to target hCA IX isozyme through the design of selective carbonic anhydrase IX inhibitors (CAIs). Here, we report the design, synthesis and biological evaluations including CA inhibition assays, toxicity assays on zebrafish and viability assays on human cell lines (HT29 and HCT116) of new HAP-CAIs, harboring different bio-reducible moieties in nitroaromatic series and a benzenesulfonamide warhead to target hCA IX. The CA inhibition assays of this compound series showed a slight selectivity against hCA IX versus the cytosolic off-target hCA II and hCA I isozymes. Toxicity and viability assays have highlighted that the compound bearing the 2-nitroimidazole moiety possesses the lowest toxicity (LC50 of 1400 µM) and shows interesting results on viability assays.

Patient specific implants for jawbone reconstruction after tumor resection

In case of benign and malignant tumours affecting the maxillofacial region, the resection of jawbone reflects the standard therapy in more than 5.000 cases per year within the European Union. The resulting large bone defects lead to scarred, mangled facial appearance, loss of mastication and probably speech, requiring aesthetic and functional surgery as a basis for physical and physiological rehabilitation. Although autologous vascularized bone autografts reflect the current golden standard, the portion of bone available for the procedure is limited and subsequent high-dose anti-cancer chemo-/radiotherapy can lead to local tissue necrosis. Autologous vascularized bone from fibular or iliac-crest autografts is current golden standard in jawbone resection post-treatment, however, the portion of transplantable bone is limited and subsequent high-dose anti-cancer chemo-/radiotherapy often results in tissue necrosis Our research focuses on alternative treatment techniques: tissue reconstruction via novel patient-specifically manufactured maxillofacial implant that stimulates bone tissue growth. The planned neoformation of vascularized bone in such implants within the patient’s own body as “bioreactor” is the safest approach in tissue engineering. The works described herein included the design of the metallic substrate of the implant with the use of computed tomography basing on real patients scans and then 3D-printing the substrates from the Ti6Al7Nb powder. The metal core was then evaluated in terms of structural characteristic, cytotoxicity and gene expression through the in vitro tests. Further experiments were focused on fabrication of the biocompatible coating for outer surface of the bone implant that would enhance the healing process and accelerate the tissue growth. Functional polymeric granulate dedicated for osteoconductive, osteoinductive and osteogenesis properties were elaborated. Another approach including the coating for the implant surface with two-phase biocompatible layer including polymeric microspheres and hydrogel carrier, which would provide long-time release of bone and cartilage growth factors around the implant were also done. The polymeric granulate containing βTCP improved bone cells growth, but it some modification has to be done in order to improve structural pores to ensure for better osteoconductivity. The biocompatible coating including PVP hydrogel and polymeric microspheres is still in the development process.

Abstract 1285A: Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters

Abstract Introduction: Erythropoietin (EPO) is a glycoprotein cytokine which stimulates red blood cell production (erythropoiesis) in the bone marrow. The receptor of it (EPOR) was reported to exist on the cancer cellular membrane: more than 85% cancer cell expresses EPOR. Several reports suggested to play an important role for cancer cellular growth, however, the role of EPOR in cancer cells is not confirmed. The authors have studied the cancer cellular porphyrin accumulation, metabolism and excretion to clear the pathogenetic mechanism which involved the high concentration of porphyrins. The authors found that reactive oxygen species (ROS) accelerate both the cancer cellular porphyrin accumulation and the effect of photodynamic therapy. However, we cannot confirm which substrate is a key of signal transduction. EPO has been known used to be up-regulated at the metabolic acidosis via the stabilization of HIF-1α, a nuclear factor. Since HIF-1α can be stabilized by not only acidosis but also the high concentration of nitric oxide (NO), NO rich cancer cells may involve EPOR. Moreover, the purpose of EPO-EPOR system is likely to survive the hypoxic condition, it may keep intracellular heme/ porphyrins. The authors’ hypothesis is EPO-EPOR system in cancer cells may down-regulate ABCG2 which excretes heme/ porphyrins, and several anti-cancer drugs. Moreover, if so, the excretion of several anti-cancer chemo reagents should be inhibited to involve more effective chemotherapy. Methods: To prove these possibilities, the authors carry out following experiments with gastric and colorectal cancer cells. The existence of EPOR, the amount of ABC transporters (B1, C5, G2) after the recombinant EPO (rEPO) exposure (dose dependency and time dependency) were analyzed by western blotting. Cytotoxicity of anti-cancer drugs with or without rEPO was measured with the Cell Counting Kit-8. Result: (1) EPOR existed in each cell line used in this study. (2) rEPO treatment involved down regulation of ABC transporters (B1, C5, G2) in dose dependently. (3) ABCG2 expression decreased until 24 hours after rEPO treatment. However, its expression re-increased 48 hours after treatment. (4) The 24 hours pretreatment of EPO significantly increased the effect of doxorubicin, paclitaxel, irrinotecan, cisplatin, 5-FU and oxaliplatin even in chemo-resistant cells. Conclusions: rEPO accelerates the effect of anti-cancer drugs via the down regulation of ABC transporters. Citation Format: Hirofumi Matsui, Hiromi Kurokawa. Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1285A.

Erythropoietin Accelerates a Cancer Specific Porphyrins' Accumulation

Introduction: Erythropoietin (EPO) is a glycoprotein cytokine which stimulates red blood cell production (erythropoiesis) in the bone marrow. The receptor of it (EPOR) was reported to exist on the cancer cellular membrane: more than 85% cancer cell expresses EPOR. Several reports suggested to play an important role for cancer cellular growth, however, the role of EPOR in cancer cells is not confirmed. The authors have studied the cancer cellular porphyrin accumulation, metabolism and excretion to clear the pathogenic mechanism which involved the high concentration of porphyrins. The authors found that reactive oxygen species (ROS) accelerate both the cancer cellular porphyrin accumulation and the effect of photodynamic therapy. However, we cannot confirm which substrate is a key of signal transduction. EPO has been known used to be up-regulated at the metabolic acidosis via the stabilization of HIF-1α, a nuclear factor. Since HIF-1α can be stabilized by not only acidosis but also the high concentration of nitric oxide (NO), NO rich cancer cells may involve EPOR. Moreover, the purpose of EPO-EPOR system is likely to survive the hypoxic condition, it may keep intracellular heme/ porphyrins. The authors’ hypothesis is EPO-EPOR system in cancer cells may down-regulate ABCG2 which excretes heme/ porphyrins, and several anti-cancer drugs. Moreover, if so, the excretion of both porphyrins and several anti-cancer chemo reagents should be inhibited to involve more effective PDT and chemotherapy. Methods: To prove these possibilities, the authors carry out following experiments with gastric and colorectal cancer cells. The existence of EPOR, the amount of ABC transporters (B1, C5, G2) after the recombinant EPO (rEPO) exposure (dose dependency and time dependency) were analyzed by western blotting. Cytotoxicity of both PDT and anti-cancer drugs with or without rEPO was measured with the Cell Counting Kit-8.Result: (1) EPOR existed in each cell line used in this study. (2) rEPO treatment involved down regulation of ABC transporters (B1, C5, G2) in dose dependently. (3) ABCG2 expression decreased until 24 hours after rEPO treatment. However, its expression re-increased 48 hours after treatment. (4) The 24 hours pretreatment of EPO significantly increased the effect of PDT, doxorubicin, paclitaxel, irrinotecan, cisplatin, 5-FU and oxaliplatin even in chemo-resistant cells.Conclusions: rEPO accelerates the effect of PDT and anti-cancer drugs via the down regulation of ABC transporters.

Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study

Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study

Lupeol: An Ubiquitous Compound for Multiple Ailments

Natural product and herbal remedies used in traditional folklore medicine have been the source of many medically beneficial drugs because they elicit fewer side effect. Lupeol is anatural products have been used as remedies to treat human diseases. It is a found in white cabbage, green pepper, strawberry, olive, mangoes and grapes. It is exhibits an array of biological activities like anticancer, antiprotozoal and cancer chemo preventive in vitro system. Last 15 years have seen tremendous efforts by researchers worldwide to develop this wonderful molecule for its clinical use for the treatment variety of disorder. It have been found to be pharmacological interaver this review highlight. In detail the therapeutic effect of Lupeol for various ailments.

Anticancer Chemodiversity of Ranunculaceae Medicinal Plants: Molecular Mechanisms and Functions.

The buttercup family, Ranunculaceae, comprising more than 2,200 species in at least 62 genera, mostly herbs, has long been used in folk medicine and worldwide ethnomedicine since the beginning of human civilization. Various medicinal phytometabolites have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anti-cancer activities in vitro and in vivo. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine. At least 17 genera have been enriched with anti-cancer phytometabolites. Some Ranunculaceae phytometabolites induce the cell cycle arrest and apoptosis of cancer cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells thereby regulating all known hallmarks of cancer. These phytometabolites could exert their anti-cancer activities via multiple signaling pathways. In addition, absorption, distribution, metabolism, and excretion/toxicity properties and structure/activity relationships of some phytometabolites have been revealed assisting in the early drug discovery and development pipelines. However, a comprehensive review of the molecular mechanisms and functions of Ranunculaceae anti-cancer phytometabolites is lacking. Here, we summarize the recent progress of the anti-cancer chemo- and pharmacological diversity of Ranunculaceae medicinal plants, focusing on the emerging molecular machineries and functions of anti-cancer phytometabolites. Gene expression profiling and relevant omics platforms (e.g. genomics, transcriptomics, proteomics, and metabolomics) could reveal differential effects of phytometabolites on the phenotypically heterogeneous cancer cells.

Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo

BackgroundBillions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. Methods & resultsUsing a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised. ConclusionsTaken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. General significanceFortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

Thermoregulatory correlates of nausea in rats and musk shrews.

Nausea is a prominent symptom and major cause of complaint for patients receiving anticancer chemo- or radiation therapy. The arsenal of anti-nausea drugs is limited, and their efficacy is questionable. Currently, the development of new compounds with anti-nausea activity is hampered by the lack of physiological correlates of nausea. Physiological correlates are needed because common laboratory rodents lack the vomiting reflex. Furthermore, nausea does not always lead to vomiting. Here, we report the results of studies conducted in four research centers to investigate whether nausea is associated with any specific thermoregulatory symptoms. Two species were studied: the laboratory rat, which has no vomiting reflex, and the house musk shrew (Suncus murinus), which does have a vomiting reflex. In rats, motion sickness was induced by rotating them in their individual cages in the horizontal plane (0.75 Hz, 40 min) and confirmed by reduced food consumption at the onset of dark (active) phase. In 100% of rats tested at three centers, post-rotational sickness was associated with marked (~1.5°C) hypothermia, which was associated with a short-lasting tail-skin vasodilation (skin temperature increased by ~4°C). Pretreatment with ondansetron, a serotonin 5-HT3 receptor antagonist, which is used to treat nausea in patients in chemo- or radiation therapy, attenuated hypothermia by ~30%. In shrews, motion sickness was induced by a cyclical back-and-forth motion (4 cm, 1 Hz, 15 min) and confirmed by the presence of retching and vomiting. In this model, sickness was also accompanied by marked hypothermia (~2°C). Like in rats, the hypothermic response was preceded by transient tail-skin vasodilation. In conclusion, motion sickness is accompanied by hypothermia that involves both autonomic and thermoeffector mechanisms: tail-skin vasodilation and possibly reduction of the interscapular brown adipose tissue activity. These thermoregulatory symptoms may serve as physiological correlates of nausea.

Preclinical Evaluation of a Novel ATM Inhibitor, KU59403, In Vitro and In Vivo in p53 Functional and Dysfunctional Models of Human Cancer

Ataxia telangiectasia mutated (ATM) kinase signals DNA double-strand breaks (DSB) to cell-cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo- and radiosensitization. KU59403 is an ATM inhibitor with the potency, selectivity, and solubility for advanced preclinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116, and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide, and doxorubicin. Chemo- and radiosensitization by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hours in tumor xenografts. KU59403 significantly enhanced the antitumor activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were nontoxic alone and well-tolerated in combination. Chemosensitization was both dose- and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to show good tissue distribution and significant chemosensitization in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle preclinical data to support the future clinical development of ATM inhibitors.